Cancer refers to a disease in which a group of cells display uncontrolled growth and proliferation due to loss of the ability to differentiate. Most of cancers are explained by the multistep carcinogenesis theory describing that mutations in oncogenes and tumor suppressor genes lead to 58-steps mutations and finally generate cancer cells. It is known that activation of cancer-causing oncogenes induces abnormal proliferation of cells, and activation of tumor suppressor genes suppresses the abnormal proliferation of cells and interrupts carcinogenesis via apoptosis, kills specific cells and inhibits generation of cancer cells.
Apoptosis is a mechanism of cell death along with necrosis. In contrast to necrosis which is caused accidentally by physical trauma, toxic chemicals, etc., it can be defined as gene-directed cellular self-destruction or programmed cell death. Multicellular organisms maintain homeostasis of cell numbers through balancing of constant cell proliferation and death. Apoptosis is the process by which the cell dies under normal physiological conditions.
The process of apoptosis may be divided into three stages according to morphological and physiological changes. In the initial stage, the cell shrinks as a result of dehydration. Blebs are formed in the cell membrane, large DNAs of 50 kb or more start degradation, and intracellular calcium level increases. In the intermediate stage, DNAs are fragmented to about 180-200 bp, displaying DNA laddering on DNA electrophoresis. In the final stage, the cell membrane completely loses its functions, and the cell is engulfed by nearby cell. It is known that the number of sub-G1 hypodiploid cells is increasing as apoptosis proceeds (Nicoletti, I., Miglorati, G., Pagliacci, M. C., Grignani, F. and Riccardi, C., J. Immunol. Methods 139(2): 271-9, 1991; Steven W. Sherwood, James P. Sheridan and Robert T. Schimke, Experimental Cell Research 215: 373-379, 1994).
Apoptosis is involved in normal development and differentiation of organisms, such as the degeneration of the tadpole tail, and is frequently seen during differentiation of fingers and toes in an embryo, menstruation, and formation of synapses between neural cells in the brain. Also, it is related with the maintenance of homeostasis, and is involved in the removal of cells infected by viruses by cytotoxic T lymphocytes.
Recently, it was found out that the suppression of cancer cell proliferation is related to the induction of apoptosis. Currently employed radiotherapies and chemotherapies, e.g. 5FU, Adriamycin and taxol, induce apoptosis in human cancer cells in vitro (K. Sugamura et al., Cancer 79: 12, 1997; S. M. Tu et al., Cancer Lett. 93: 147, 1995; R. M. Gangemi et al., Science 784: 550, 1990).
Thus, researches on substances that can induce apoptosis in cancer cells for use as anticancer agent are actively carried out. For example, Korean Patent Publication No. 2004-59495 discloses a composition inducing apoptosis of cancer cells, which includes Agaricus extract, and Korean Patent Publication No. 2001-7007571 discloses 7-aryl-6(Z)-heptatrienoic acid retinamide as a compound inducing apoptosis of cancer cells. However, these anticancer agents are not widely used. In addition, they are known to kill not only the cancer cells but also normal cells.
Although the glycyl-tRNA synthetase (GRS) protein is known as a protein involved in the synthesis of aminoacyl tRNA, nothing is known about the anticancer activity of the protein.